Humans are naturally resistant to infection by the African trypanosome prototype Trypanosoma brucei brucei, and only two variant clones of this parasite can avoid this innate immunity and cause sleeping sickness. The resistance to T. brucei is due to serum complexes associating apolipoprotein A-1 (apoA1) with two primate-specific proteins, apolipoprotein L-1 (apoL1) and haptoglobin-related protein (Hpr). We discuss recent advances on the respective functions of apoL1 and Hpr in this system. ApoL1 was found to share structural and functional similarities with proteins of the apoptotic Bcl2 family, and to kill trypanosomes through anionic pore formation in the lysosomal membrane of the parasite. In association with hemoglobin (Hb), Hpr was found to promote the binding of the trypanolytic complexes to a haptoglobin (Hp)–Hb receptor of the trypanosome surface, hereby facilitating the internalization of apoL1. Hpr or apoL1 deficiency respectively leads to the reduction or abolishment of human protection against T. brucei.